CRF, a 4l-amino acid peptide, plays a significant role in modulating inflammatory responses through its coordinated actions in the nervous, endocrine and immune systems. CRF has indirect anti-inflammatory effects through stimulation of the pituitary- adrenocortical axis resulting in glucocorticoid secretion. In addition, recent preclinical and clinical data suggest important autocrine/paracrine pro-inflammatory roles for CRF in arthritis. Thus, therapies to inactivate and/or block the effects of local overproduction of CRF at inflammatory sites may represent novel agents for the treatment of rheumatoid arthritis and other inflammatory conditions. A circulating form of a human binding protein with high affinity for CRF and the ability to inactivate CRF has been recently purified and cloned. The studies of the proposal are aimed at evaluating the potential anti-inflammatory effects of the human CRF-BP. The efficacy of CRF- BP will be evaluated in two rat models of acute inflammation (carrageenin- and oyster-glycogen induced inflammation) and in two rat chronic models of arthritis (streptococcal cell wall- and adjuvant-induced arthritis). The study will also include pilot feasibility studies to work out the best methodology for recombinant expression and purification of scale-up quantities of the CRF-binding protein and the development of assay systems for detection of immunoreactive and biologically active forms of the human CRF-binding protein. The second phase of the study will involve clinical studies to evaluate the anti-inflammatory actions of CRF-binding protein in rheumatoid arthritis patients. In addition, orally active, small molecule non-peptide CRF receptor antagonists will be identified as second generation agents for the treatment of rheumatoid arthritis.